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Trial registered on ANZCTR


Registration number
ACTRN12613000322730
Ethics application status
Approved
Date submitted
8/03/2013
Date registered
22/03/2013
Date last updated
24/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Hypoglycaemia Prevention in Newborns with Oral Dextrose: the dosage trial
Scientific title
In newborn infants at risk of hypoglycaemia does prophylactic oral dextrose gel compared to placebo reduce the incidence of hypoglycaemia (any blood glucose concentration < 2.6 mM).
Secondary ID [1] 281706 0
nil known
Universal Trial Number (UTN)
U1111-1138-0836
Trial acronym
pre-hPOD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neonatal Hypoglycaemia 287998 0
Condition category
Condition code
Metabolic and Endocrine 288378 288378 0 0
Other metabolic disorders
Reproductive Health and Childbirth 289018 289018 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This trial is a dosage trial to determine the most effective dose and frequency of 40% dextrose gel in preventing hypoglycaemia.

There will be 8 arms, 4 intervention and 4 placebo.

All doses will be administered by massage into the buccal mucosa immediately prior to a breastfeed, beginning with the first feed no later than one hour after birth.

Intervention arms - 40% dextrose:
Arm 1 Single dose arm; 200mg/kg (0.5ml/kg) before first feed
Arm 2 Multiple dose arm; 200mg/kg (0.5ml/kg) given pre-feed, before the first four feeds
Arm 3 Single, higher dose arm; 400mg/kg (1ml/kg) before first feed
Arm 4 Multiple, higher dose arm; 400mg/kg (1ml/kg) before first feed, followed by 200mg/kg (0.5ml/kg), given pre-feed, before the next three feeds

The most effective dose will subsequently be used in a multicentre trial with a primary outcome of reduction in admission to NICU. The multicentre trial will be registered with ANZCTR separately.
Intervention code [1] 286242 0
Prevention
Comparator / control treatment
Placebo - 2% hydroxymethylcellulose gel

All doses will be administered by massage into the buccal mucosa immediately prior to a breastfeed, beginning with the first feed no later than one hour after birth.

Arm 1 Single dose arm; 0.5ml/kg before the first feed
Arm 2 Multiple dose arm; 0.5ml/kg given pre-feed, before the first four feeds
Arm 3 Single, higher dose arm; 1ml/kg before the first feed
Arm 4 Multiple, higher dose arm; 1ml/kg before the first feed, followed by 0.5ml/kg given pre-feed, before the next three feeds
Control group
Placebo

Outcomes
Primary outcome [1] 288549 0
Incidence of neonatal hypoglycaemia (any blood glucose concentration <2.6mM measured by the glucose oxidase method).
Timepoint [1] 288549 0
In the first 48 hours after birth.
Secondary outcome [1] 300443 0
Admission to NICU, defined as admission to Neonatal Intensive Care Unit (NICU), or Special Care Baby Unit (SCBU) for the hospitals which use that name, for > 4 hours, determined from medical records.
Timepoint [1] 300443 0
Prior to discharge home.
Secondary outcome [2] 301763 0
Admission to NICU or SCBU for > 4 hours duration, where the primary reason for admission is hypoglycaemia.
Timepoint [2] 301763 0
Prior to discharge home.
Secondary outcome [3] 301764 0
Hyperglycaemia (any blood glucose concentration of > 10mmol/l measured by the glucose oxidase method).
Timepoint [3] 301764 0
In the first 48 hours after birth.
Secondary outcome [4] 301765 0
Breastfeeding (full or exclusive), determined by parental questionnaire.
Timepoint [4] 301765 0
At day 3 and 6 weeks after birth.
Secondary outcome [5] 301766 0
Received any formula before day 3 and 6 weeks after birth, determined by parental questionnaire.
Timepoint [5] 301766 0
At day 3 and 6 weeks after birth.
Secondary outcome [6] 301767 0
Formula feeding at day 3 and 6 weeks after birth, determined by parental questionnaire.
Timepoint [6] 301767 0
At day 3 and 6 weeks after birth.
Secondary outcome [7] 301768 0
Economic cost of healthcare to discharge, determined using resource utilisation data from clinical records.
Timepoint [7] 301768 0
At discharge to home.
Secondary outcome [8] 301769 0
Maternal satisfaction, determined by parental questionnaire.
Timepoint [8] 301769 0
On day 3 and 6 weeks of age.

Eligibility
Key inclusion criteria
Babies who are at risk of hypoglycaemia, defined as satisfying AT LEAST ONE of the following:
1. Infants of diabetic mothers (any type of diabetes)
2. Preterm (< 37 weeks' gestation)
3. Small (< 2.5kg or < 10th centile on population or customised birthweight chart)
4. Large (> 4.5kg or > 90th centile on population or customised birthweight chart)
5. Other risk e.g. maternal medication

AND satisfy ALL of the following:
1. > or = 35+0 weeks' gestation
2. Birthweight > 2.2kg
3. < 1 hour old
4. No apparent indication for NICU/SCBU admission at time of randomisation
5. Unlikely to require admission to NICU/SCBU for any other reason e.g. respiratory distress
6. Mother intending to breastfeed.
Minimum age
0 Hours
Maximum age
1 Hours
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Major congenital abnormality
2. Previous formula feed or intravenous fluids
3. Previous diagnosis of hypoglycaemia
4. Admitted to NICU/SCBU
5. Imminent admission to NICU/SCBU

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Enrolling: Parents of babies who are likely to become eligible (maternal diabetes, likely late preterm birth, or anticipated high or low birthweight) will be identified through lead maternity carers and antenatal clinics and provided with an information sheet as early as is feasible. Written informed consent will normally be obtained before birth by a member of the research team.

Allocation to intervention will be by central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Minimisation for dosage trial

Stratification for:-
1. Centre
2. Risk Factor i.e. Infant of diabetic/preterm/small/large/other risk factor
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The aim of this trial is to assist the hPOD steering committee by recommending the optimal dose regimen for the main hPOD trial (a separate Phase III trial registered with this ANZCTR). This decision will be a synthesis of the dose required for adequate efficacy with a minimal burden of side-effects and pragmatically consider the ease of administration, simplicity and tolerance of the intervention and cost.
Efficacy has been pre-specified as a reduction in the proportion of babies with at least one episode of hypoglycaemia from an estimated absolute 50% anticipated in the trial cohort to 25%.
To visualise the association between dose and outcome the cumulative administered dose for the single and multiple dose arms (i.e. 0, 200, 400, 800 and 1000 mg/kg) will be plotted as the independent variable. The response to single placebo dose (0 mg/kg) and multiple placebo doses (0 mg/kg x 4 feeds) for each dependent variable will be compared (Fisher’s exact test) and the magnitude of any difference considered for clinical relevance.
Logistic regression modelling the odds of hypoglycaemia for each cumulative dose of glucose and the multiple dose placebo arm relative to the single dose placebo arm will be plotted (with 95% confidence intervals) as the dependent variable against cumulative glucose dose (the independent variable). This analysis will adjust for risk factors for hypoglycaemia (i.e. sex, gestational age and mode of delivery).
It is likely that these data will yield a number of ‘possible’ doses where either the 95% confidence interval for the odds of reduced hypoglycaemia is significantly lower than the placebo dose (i.e. P odds of hypoglycaemia < 0.05). Therefore a complementary analysis of limitations at each dose level will be considered.
The odds of at least one limitation (tolerance or length of time to administer dose or messiness or hyperglycaemia or late hypoglycaemia or delayed feeding or unacceptability to parent(s)) for each cumulative dose arm relative to the placebo dose will be estimated (with 95% confidence intervals) and plotted and the likelihood that this estimate differs from the placebo arm reported. Additionally a limitation score, comprising the sum of weights assigned to the predetermined limitations will be summarised for each cumulative dose arm (median +/- 95% confidence interval Mid-P method) and plotted. Data will be examined four times: after 120, 240 and 360 patients have been accrued and at the end of recruitment by the Data Monitoring Committee.
Analyses will be performed using SAS (v9.3 SAS Institute Inc). All tests will be two tailed and p < 0.05 will be considered statistically significant. Since these are exploratory analyses no adjustment for multiplicity will be performed.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 4769 0
New Zealand
State/province [1] 4769 0

Funding & Sponsors
Funding source category [1] 286494 0
Charities/Societies/Foundations
Name [1] 286494 0
Cure Kids
Address [1] 286494 0
PO Box 90 907
Victoria Street West
Auckland 1142
Country [1] 286494 0
New Zealand
Funding source category [2] 286495 0
Charities/Societies/Foundations
Name [2] 286495 0
Auckland DHB Charitable Trust, A+ Trust Research Grant
Address [2] 286495 0
Research Office
Level 14, Support Bldg, Auckland City Hospital.
Private Bag 92024, Auckland 1023
New Zealand
Country [2] 286495 0
New Zealand
Funding source category [3] 286496 0
Charities/Societies/Foundations
Name [3] 286496 0
University of Auckland Foundation
Address [3] 286496 0
c/- External Relations, The University of Auckland
Private Bag 92019, Auckland 1142
Country [3] 286496 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
The University of Auckland
Private Bag 92019
Auckland 1142
New Zealand
Country
New Zealand
Secondary sponsor category [1] 285284 0
None
Name [1] 285284 0
Address [1] 285284 0
Country [1] 285284 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288572 0
Health and Disability Ethics Committees
Ethics committee address [1] 288572 0
Ministry of Health
No 1 The Terrace
PO Box 5013
Wellington 6011
Ethics committee country [1] 288572 0
New Zealand
Date submitted for ethics approval [1] 288572 0
29/01/2013
Approval date [1] 288572 0
15/02/2013
Ethics approval number [1] 288572 0
13/NTA/8

Summary
Brief summary
Hypoglycaemia is the commonest metabolic condition of the newborn. It affects up to 15% of babies, and the incidence is increasing as risk factors such as maternal diabetes and preterm birth are becoming more common. Neonatal hypoglycaemia frequently leads to neonatal intensive care unit (NICU) admission and may cause long-term brain damage. There currently are no evidence-based strategies to prevent hypoglycaemia and its adverse consequences.

The purpose of this trial is to find the dose of prophylactic oral dextrose gel which will prevent neonatal hypoglycaemia when administered to newborn babies at risk of hypoglycaemia. The most effective, acceptable and safe dose of dextrose gel will be used in a multicentre trial to determine whether prophylactic dextrose gel prevents admission to NICU.
Trial website
Trial related presentations / publications
Hegarty JE, Harding JE, Gamble G, Crowther CA, Edlin R, Alsweiler JM. Oral Dextrose Gel to Prevent Neonatal Hypoglycaemia in Newborn Babies at Risk: a Randomised Controlled Dose-Finding Trial (The pre-hPOD Study). PLoS Medicine 2016, 13(10):e1002155
http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002155
Public notes

Contacts
Principal investigator
Name 36730 0
Prof Jane Harding
Address 36730 0
Liggins Institute
2-6 Park Avenue,
Private Bag 92019
Auckland 1142
Country 36730 0
New Zealand
Phone 36730 0
+64 9 3737599 ext 85872
Fax 36730 0
Email 36730 0
j.harding@auckland.ac.nz
Contact person for public queries
Name 36731 0
Prof Jane Harding
Address 36731 0
Liggins Institute
2-6 Park Avenue,
Private Bag 92019
Auckland 1142
Country 36731 0
New Zealand
Phone 36731 0
+64 9 3737599 ext 85872
Fax 36731 0
Email 36731 0
j.harding@auckland.ac.nz
Contact person for scientific queries
Name 36732 0
Prof Jane Harding
Address 36732 0
Liggins Institute
2-6 Park Avenue,
Private Bag 92019
Auckland 1142
Country 36732 0
New Zealand
Phone 36732 0
+64 9 3737599 ext 85872
Fax 36732 0
Email 36732 0
j.harding@auckland.ac.nz

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary